scholarly journals Ceramide synthases at the centre of sphingolipid metabolism and biology

2012 ◽  
Vol 441 (3) ◽  
pp. 789-802 ◽  
Author(s):  
Thomas D. Mullen ◽  
Yusuf A. Hannun ◽  
Lina M. Obeid
Keyword(s):  
Cell Death ◽  
De Novo ◽  
Acyl Chain ◽  
Sphingolipid Metabolism ◽  
Sphingoid Base ◽  
Salvage Pathway ◽  
Organismal Biology ◽  
Acyl Chain Length ◽  
Specific Manner ◽  
Ceramide Synthases

Sphingolipid metabolism in metazoan cells consists of a complex interconnected web of numerous enzymes, metabolites and modes of regulation. At the centre of sphingolipid metabolism reside CerSs (ceramide synthases), a group of enzymes that catalyse the formation of ceramides from sphingoid base and acyl-CoA substrates. From a metabolic perspective, these enzymes occupy a unique niche in that they simultaneously regulate de novo sphingolipid synthesis and the recycling of free sphingosine produced from the degradation of pre-formed sphingolipids (salvage pathway). Six mammalian CerSs (CerS1–CerS6) have been identified. Unique characteristics have been described for each of these enzymes, but perhaps the most notable is the ability of individual CerS isoforms to produce ceramides with characteristic acyl-chain distributions. Through this control of acyl-chain length and perhaps in a compartment-specific manner, CerSs appear to regulate multiple aspects of sphingolipid-mediated cell and organismal biology. In the present review, we discuss the function of CerSs as critical regulators of sphingolipid metabolism, highlight their unique characteristics and explore the emerging roles of CerSs in regulating programmed cell death, cancer and many other aspects of biology.

The effect of altered sphingolipid acyl chain length on various disease models

2015 ◽  
Vol 396 (6-7) ◽  
pp. 693-705 ◽  
Author(s):  
Woo-Jae Park ◽  
Joo-Won Park
Keyword(s):  
Chain Length ◽  
De Novo ◽  
Case Reports ◽  
Acyl Chain ◽  
Fatty Acyl ◽  
Sphingolipid Metabolism ◽  
Lipid Mediator ◽  
Disease Models ◽  
Acyl Chain Length ◽  
Sphingosine 1 Phosphate

Abstract Sphingolipids have emerged as an important lipid mediator in intracellular signalling and metabolism. Ceramide, which is central to sphingolipid metabolism, is generated either via a de novo pathway, by attaching fatty acyl CoA to a long-chain base, or via a salvage pathway, by degrading pre-existing sphingolipids. As a ‘sphingolipid rheostat’ has been proposed, the balance between ceramide and sphingosine-1-phosphate has been the object of considerable attention. Ceramide has recently been reported to have a different function depending on its acyl chain length: six ceramide synthases (CerS) determine the specific ceramide acyl chain length in mammals. All CerS-deficient mice generated to date show that sphingolipids with defined acyl chain lengths play distinct pathophysiological roles in disease models. This review describes recent advances in understanding the associations of CerS with various diseases and includes clinical case reports.

scholarly journals Inactivation of Ceramide Synthase 6 in Mice Results in an Altered Sphingolipid Metabolism and Behavioral Abnormalities

2013 ◽  
Vol 288 (29) ◽  
pp. 21433-21447 ◽  
Author(s):  
Philipp Ebel ◽  
Katharina vom Dorp ◽  
Elisabeth Petrasch-Parwez ◽  
Armin Zlomuzica ◽  
Kiyoka Kinugawa ◽  
...  
Keyword(s):  
Expression Patterns ◽  
Acyl Chain ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
Acyl Chain Length ◽  
Hind Limbs ◽  
Behavioral Abnormalities ◽  
Ceramide Content ◽  
Ceramide Synthases ◽  
The Brain

The N-acyl chain length of ceramides is determined by the specificity of different ceramide synthases (CerS). The CerS family in mammals consists of six members with different substrate specificities and expression patterns. We have generated and characterized a mouse line harboring an enzymatically inactive ceramide synthase 6 (CerS6KO) gene and lacz reporter cDNA coding for β-galactosidase directed by the CerS6 promoter. These mice display a decrease in C16:0 containing sphingolipids. Relative to wild type tissues the amount of C16:0 containing sphingomyelin in kidney is ∼35%, whereas we find a reduction of C16:0 ceramide content in the small intestine to about 25%. The CerS6KO mice show behavioral abnormalities including a clasping abnormality of their hind limbs and a habituation deficit. LacZ reporter expression in the brain reveals CerS6 expression in hippocampus, cortex, and the Purkinje cell layer of the cerebellum. Using newly developed antibodies that specifically recognize the CerS6 protein we show that the endogenous CerS6 protein is N-glycosylated and expressed in several tissues of mice, mainly kidney, small and large intestine, and brain.

scholarly journals Altering Sphingolipid Metabolism Attenuates Cell Death and Inflammatory Response After Myocardial Infarction

Circulation ◽  
2020 ◽  
Vol 141 (11) ◽  
pp. 916-930 ◽  
Author(s):  
Yoav Hadas ◽  
Adam S. Vincek ◽  
Elias Youssef ◽  
Magdalena M. Żak ◽  
Elena Chepurko ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Death ◽  
Left Ventricle ◽  
Cell Survival ◽  
Immune Cell ◽  
De Novo ◽  
Therapeutic Potential ◽  
Heart Function ◽  
Sphingolipid Metabolism ◽  
Death Rates

Background: Sphingolipids have recently emerged as a biomarker of recurrence and mortality after myocardial infarction (MI). The increased ceramide levels in mammalian heart tissues during acute MI, as demonstrated by several groups, is associated with higher cell death rates in the left ventricle and deteriorated cardiac function. Ceramidase, the only enzyme known to hydrolyze proapoptotic ceramide, generates sphingosine, which is then phosphorylated by sphingosine kinase to produce the prosurvival molecule sphingosine-1-phosphate. We hypothesized that Acid Ceramidase (AC) overexpression would counteract the negative effects of elevated ceramide and promote cell survival, thereby providing cardioprotection after MI. Methods: We performed transcriptomic, sphingolipid, and protein analyses to evaluate sphingolipid metabolism and signaling post-MI. We investigated the effect of altering ceramide metabolism through a loss (chemical inhibitors) or gain (modified mRNA [modRNA]) of AC function post hypoxia or MI. Results: We found that several genes involved in de novo ceramide synthesis were upregulated and that ceramide (C16, C20, C20:1, and C24) levels had significantly increased 24 hours after MI. AC inhibition after hypoxia or MI resulted in reduced AC activity and increased cell death. By contrast, enhancing AC activity via AC modRNA treatment increased cell survival after hypoxia or MI. AC modRNA-treated mice had significantly better heart function, longer survival, and smaller scar size than control mice 28 days post-MI. We attributed the improvement in heart function post-MI after AC modRNA delivery to decreased ceramide levels, lower cell death rates, and changes in the composition of the immune cell population in the left ventricle manifested by lowered abundance of proinflammatory detrimental neutrophils. Conclusions: Our findings suggest that transiently altering sphingolipid metabolism through AC overexpression is sufficient and necessary to induce cardioprotection post-MI, thereby highlighting the therapeutic potential of AC modRNA in ischemic heart disease.

scholarly journals The elongation of exogenous fatty acids and the control of phospholipid acyl chain length in Micrococcus cryophilus

1980 ◽  
Vol 188 (3) ◽  
pp. 585-592 ◽  
Author(s):  
S P Sandercock ◽  
N J Russell
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Chain Length ◽  
De Novo ◽  
Acyl Chain ◽  
Psychrophilic Bacterium ◽  
Fatty Acid Elongation ◽  
Acyl Chain Length ◽  
Acyl Chains ◽  
Phospholipid Acyl Chain

The synthesis of fatty acids de novo from acetate and the elongation of exogenous satuated fatty acids (C12-C18) by the psychrophilic bacterium Micrococcus cryophilus (A.T.C.C. 15174) grown at 1 or 20 degrees C was investigated. M. cryophilus normally contains only C16 and C18 acyl chains in its phospholipids, and the C18/C16 ratio is altered by changes in growth temperature. The bacterium was shown to regulate strictly its phospholipid acyl chain length and to be capable of directly elongating myristate and palmitate, and possibly laurate, to a mixture of C16 and C18 acyl chains. Retroconversion of stearate into palmitate also occurred. Fatty acid elongation could be distinguished from fatty acid synthesis de novo by the greater sensitivity of fatty acid elongation to inhibition by NaAsO2 under conditions when the supply of ATP and reduced nicotinamide nucleotides was not limiting. It is suggested that phospholipid acyl chain length may be controlled by a membrane-bound elongase enzyme, which interconverts C16 and C18 fatty acids via a C14 intermediate; the activity of the enzyme could be regulated by membrane lipid fluidity.

scholarly journals Ceramide Synthesis Is Modulated by the Sphingosine Analog FTY720 via a Mixture of Uncompetitive and Noncompetitive Inhibition in an Acyl-CoA Chain Length-de pend ent Manner

2009 ◽  
Vol 284 (24) ◽  
pp. 16090-16098 ◽  
Author(s):  
Sujoy Lahiri ◽  
Hyejung Park ◽  
Elad L. Laviad ◽  
Xuequan Lu ◽  
Robert Bittman ◽  
...  
Keyword(s):  
Chain Length ◽  
Cultured Cells ◽  
De Novo ◽  
Biological Effects ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
Noncompetitive Inhibition ◽  
Ceramide Synthesis ◽  
Ceramide Synthases

FTY720, a sphingosine analog, is in clinical trials as an immunomodulator. The biological effects of FTY720 are believed to occur after its metabolism to FTY720 phosphate. However, very little is known about whether FTY720 can interact with and modulate the activity of other enzymes of sphingolipid metabolism. We examined the ability of FTY720 to modulate de novo ceramide synthesis. In mammals, ceramide is synthesized by a family of six ceramide synthases, each of which utilizes a restricted subset of acyl-CoAs. We show that FTY720 inhibits ceramide synthase activity in vitro by noncompetitive inhibition toward acyl-CoA and uncompetitive inhibition toward sphinganine; surprisingly, the efficacy of inhibition depends on the acyl-CoA chain length. In cultured cells, FTY720 has a more complex effect, with ceramide synthesis inhibited at high (500 nm to 5 μm) but not low (<200 nm) sphinganine concentrations, consistent with FTY720 acting as an uncompetitive inhibitor toward sphinganine. Finally, electrospray ionization-tandem mass spectrometry demonstrated, unexpectedly, elevated levels of ceramide, sphingomyelin, and hexosylceramides after incubation with FTY720. Our data suggest a novel mechanism by which FTY720 might mediate some of its biological effects, which may be of mechanistic significance for understanding its mode of action.

scholarly journals Overexpression of Arabidopsis Ceramide Synthases Differentially Affects Growth, Sphingolipid Metabolism, Programmed Cell Death, and Mycotoxin Resistance

2015 ◽  
Vol 169 (2) ◽  
pp. 1108-1117 ◽  
Author(s):  
Kyle D. Luttgeharm ◽  
Ming Chen ◽  
Amit Mehra ◽  
Rebecca E. Cahoon ◽  
Jonathan E. Markham ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthases

scholarly journals Lipids and Trehalose Actively Cooperate in Heat Stress Management of Schizosaccharomyces pombe

2021 ◽  
Vol 22 (24) ◽  
pp. 13272
Author(s):  
Mária Péter ◽  
Péter Gudmann ◽  
Zoltán Kóta ◽  
Zsolt Török ◽  
László Vígh ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Heat Stress ◽  
Schizosaccharomyces Pombe ◽  
De Novo ◽  
Acyl Chain ◽  
Membrane Lipid ◽  
Yeast Cells ◽  
Storage Lipids ◽  
Acyl Chain Length

Homeostatic maintenance of the physicochemical properties of cellular membranes is essential for life. In yeast, trehalose accumulation and lipid remodeling enable rapid adaptation to perturbations, but their crosstalk was not investigated. Here we report about the first in-depth, mass spectrometry-based lipidomic analysis on heat-stressed Schizosaccharomyces pombe mutants which are unable to synthesize (tps1Δ) or degrade (ntp1Δ) trehalose. Our experiments provide data about the role of trehalose as a membrane protectant in heat stress. We show that under conditions of trehalose deficiency, heat stress induced a comprehensive, distinctively high-degree lipidome reshaping in which structural, signaling and storage lipids acted in concert. In the absence of trehalose, membrane lipid remodeling was more pronounced and increased with increasing stress dose. It could be characterized by decreasing unsaturation and increasing acyl chain length, and required de novo synthesis of stearic acid (18:0) and very long-chain fatty acids to serve membrane rigidification. In addition, we detected enhanced and sustained signaling lipid generation to ensure transient cell cycle arrest as well as more intense triglyceride synthesis to accommodate membrane lipid-derived oleic acid (18:1) and newly synthesized but unused fatty acids. We also demonstrate that these changes were able to partially substitute for the missing role of trehalose and conferred measurable stress tolerance to fission yeast cells.

scholarly journals Hepatic triglyceride accumulation via endoplasmic reticulum stress-induced SREBP-1 activation is regulated by ceramide synthases

2019 ◽  
Vol 51 (11) ◽  
pp. 1-16 ◽  
Author(s):  
Ye-Ryung Kim ◽  
Eun-Ji Lee ◽  
Kyong-Oh Shin ◽  
Min Hee Kim ◽  
Yael Pewzner-Jung ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Acyl Chain ◽  
Protective Role ◽  
Sphingolipid Metabolism ◽  
Er Stress Response ◽  
Triglyceride Accumulation ◽  
Ceramide Synthases

Abstract The endoplasmic reticulum (ER) is not only important for protein synthesis and folding but is also crucial for lipid synthesis and metabolism. In the current study, we demonstrate an important role of ceramide synthases (CerS) in ER stress and NAFLD progression. Ceramide is important in sphingolipid metabolism, and its acyl chain length is determined by a family of six CerS in mammals. CerS2 generates C22-C24 ceramides, and CerS5 or CerS6 produces C16 ceramide. To gain insight into the role of CerS in NAFLD, we used a high-fat diet (HFD)-induced NAFLD mouse model. Decreased levels of CerS2 and increased levels of CerS6 were observed in the steatotic livers of mice fed a HFD. In vitro experiments with Hep3B cells indicated the protective role of CerS2 and the detrimental role of CerS6 in the ER stress response induced by palmitate treatment. In particular, CerS6 overexpression increased sterol regulatory element-binding protein-1 (SREBP-1) cleavage with decreased levels of INSIG-1, leading to increased lipogenesis. Blocking ER stress abrogated the detrimental effects of CerS6 on palmitate-induced SREBP-1 cleavage. In accordance with the protective role of CerS2 in the palmitate-induced ER stress response, CerS2 knockdown enhanced ER stress and SREBP-1 cleavage, and CerS2 heterozygote livers exhibited a stronger ER stress response and higher triglyceride levels following HFD. Finally, treatment with a low dose of bortezomib increased hepatic CerS2 expression and protected the development of NAFLD following HFD. These results indicate that CerS and its derivatives impact hepatic ER stress and lipogenesis differently and might be therapeutic targets for NAFLD.

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